Cutaneous adverse effects of targeted therapies: Part I: Inhibitors of the cellular membrane.

There has been a rapid emergence of numerous targeted agents in the oncology community in the last decade. This exciting paradigm shift in drug development lends promise for the future of individualized medicine. Given the pace of development and clinical deployment of targeted agents with novel mechanisms of action, dermatology providers may not be familiar with the full spectrum of associated skin-related toxicities. Cutaneous adverse effects are among the most frequently observed toxicities with many targeted agents, and their intensity can be dose-limiting or lead to therapy discontinuation. In light of the often life-saving nature of emerging oncotherapeutics, it is critical that dermatologists both understand the mechanisms and recognize clinical signs and symptoms of such toxicities in order to provide effective clinical management. Part I of this continuing medical education article will review in detail the potential skin-related adverse sequelae, the frequency of occurrence, and the implications associated with on- and off-target cutaneous toxicities of inhibitors acting at the cell membrane level, chiefly inhibitors of epidermal growth factor receptor, KIT, and BCR-ABL, angiogenesis, and multikinase inhibitors.

Cutaneous adverse effects of targeted therapies: Part II: Inhibitors of intracellular molecular signaling pathways.

The last decade has spawned an exciting new era of oncotherapy in dermatology, including the development of targeted therapies for metastatic melanoma and basal cell carcinoma. Along with skin cancer, deregulation of the PI3K-AKT-mTOR and RAS-RAF-MEK-ERK intracellular signaling pathways contributes to tumorigenesis of a multitude of other cancers, and inhibitors of these pathways are being actively studied. Similar to other classes of targeted therapies, cutaneous adverse effects are among the most frequent toxicities observed with mitogen-activated protein kinase pathway inhibitors, PI3K-AKT-mTOR inhibitors, hedgehog signaling pathway inhibitors, and immunotherapies. Given the rapid expansion of these families of targeted treatments, dermatologists will be essential in offering dermatologic supportive care measures to cancer patients being treated with these agents. Part II of this continuing medical education article reviews skin-related adverse sequelae, including the frequency of occurrence and the implications associated with on- and off-target cutaneous toxicities of inhibitors of the RAS-RAF-MEK-ERK pathway, PI3K-AKT-mTOR pathway, hedgehog signaling pathway, and immunotherapies.

Who sends what: a comparison of dermatopathology referrals from dermatologists, pathologists and dermatopathologists.

BACKGROUND: Dermatopathologists, dermatologists and pathologists interpret skin pathology specimens. OBJECTIVE: To examine dermatopathology referral patterns of dermatologists, pathologists and dermatopathologists. METHODS: We retrospectively reviewed diagnoses rendered by one dermatopathologist to 916 primary interpretation cases (543 from university dermatologists and 373 from private practice dermatologists) and 517 consultations (450 from dermatologists, 52 from pathologists and 15 from dermatopathologists). Each diagnosis was assigned into one of six categories. Chi-square tests were used to compare referral types pairwise and correspondence analysis was performed. RESULTS: All profile comparisons tested significantly from each other (p-value < 0.01) except the comparison between dermatopathologists and pathologists. Correspondence analysis suggested that consultation profile of dermatopathologists was most dissimilar from other profiles and tended to associate more with the presence of malignant and benign melanocytic referral types. Referral pattern of pathologists was more similar to that of dermatologists who interpret skin pathology specimens than that of dermatopathologists. LIMITATIONS: Small sample size, referral bias, difficulty classifying certain lesions. CONCLUSIONS: Referral pattern of dermatopathologists was most dissimilar from other profiles and tended to associate more with malignant and benign melanocytic referral types. Referral pattern of pathologists was more similar to that of dermatologists who interpret skin pathology specimens than that of dermatopathologists.

Hyalinized collagen in a dermatofibrosarcoma protuberans after treatment with imatinib mesylate.

We report a novel histological finding in a dermatofibrosarcoma protuberans (DFSP) after treatment with imatinib mesylate: copious amounts of hyalinized collagen. A 57-year-old female was referred for evaluation and treatment of a 7 x 8 x 10 cm tumor on the right anterior shoulder. Histological evaluation of the incisional biopsy showed a highly cellular dermal neoplasm composed of spindle cells arranged in a storiform pattern with minimal collagen. A CD34 immunohistochemical stain was strongly positive, highlighting atypical spindle cells in the dermis. A diagnosis of DFSP was made and the patient was enrolled in the Southwest Oncology Group trial. She received imatinib mesylate 400 mg per day for 1 year. At the end of therapy, the DFSP decreased in size to 5.5 x 4 x 4 cm. The tumor was excised. Histological evaluation showed a residual dermal neoplasm composed of atypical spindle cells and a copious amount of hyalinized collagen. Areas of necrosis were not seen. A CD34 stain confirmed the presence of residual DFSP, highlighting atypical spindle cells. A procollagen I stain was strongly positive, confirming the presence of abundant collagen in the dermis. A similar finding has been reported in gastrointestinal stromal tumor, which shows deposition of myxohyaline stroma after treatment with imatinib mesylate.

Unusual presentation of ectopic extramammary Paget disease.

Extramammary Paget disease (EMPD) is a malignant tumor typically found in apocrine-rich areas of the skin, particularly in the anogenital region. Some germinative apocrine-differentiating cells might exist on the trunk, preferentially in Asian individuals. Ectopic EMPD arises in nonapocrine-bearing areas, specifically the nongerminative milk line. We present a case of a 67-year-old Thai man with a slowly progressive, pruritic, erythematous to brown plaque on the right lower back of 30 years' duration. Histopathologic examination of 2 scouting biopsies revealed a proliferation of large cells with pleomorphic nuclei, prominent nucleoli, and abundant pale to clear cytoplasm within the epidermis. In one of the biopsies, tumor cells were found in the dermis with an infiltrative growth pattern. Immunohistochemically, the tumor cells were positive for cytokeratin 7, carcinoembryonic antigen, and gross cystic disease fluid protein 15. Based on these findings, a diagnosis of ectopic EMPD was made.

Is melanocytic nevus with focal atypical epithelioid components (clonal nevus) a superficial variant of deep penetrating nevus?

BACKGROUND: We compare features of two similar nevi which may be confused with melanoma: deep penetrating nevus (DPN), and nevus with focal atypical epithelioid component (NFAEC). METHODS: Clinical/demographic and histologic information regarding 146 DPN and 81 NFAEC were compared. Patient outcomes were ascertained via a questionnaire solicited to the referring physicians. RESULTS: Clinical features were similar for each type of nevus. Histologically, all lesions demonstrated identical aggregates of epithelioid melanocytes. DPN more often extended into the deep dermis or subcutaneous tissue, while NFAEC was typically confined to the superficial dermis. NFAEC more often demonstrated a junctional component (P < .001) and coexistent common nevus with congenital features (P = .035). DPN more often demonstrated adnexal spread (P < .001). A subgroup with overlapping features was identified. With an average of 6.4 years follow-up, there were just two recurrences, and no metastases. LIMITATIONS: This retrospective study utilized tissue specimens from a single reference laboratory; ergo, some inherent selection bias exists. Specimens were randomly selected for P53 immunostaining, leading also to potential sampling error. CONCLUSIONS: DPN and NFAEC show considerable similarity, differing mainly in the depth of extent for the lesion. It is possible that NFAEC represents a more superficial variant of DPN. A subgroup with overlapping features, but intermediate depth, supports such a relationship.

Association of expression of CD44v6 with systemic anaplastic large cell lymphoma: comparison with primary cutaneous anaplastic large cell lymphoma.

CD44 is a ubiquitous multifunctional cell surface adhesion molecule family. High expression of the standard form, CD44s (CD44), and its variant form, CD44v6, has been reported to be associated with tumor dissemination in non-Hodgkin lymphoma. To evaluate the potential role of CD44 and/or CD44v6 in different entities of anaplastic large cell lymphoma (ALCL), 30 cases of systemic ALCL (sALCL; 20 cases) and primary cutaneous ALCL (cALCL; 10 cases) were compared for expression of CD44 and CD44v6 by immunohistochemical staining. Expression of CD44v6 also was analyzed with respect to expression of anaplastic lymphoma kinase (ALK) in sALCL. No difference of CD44 expression was noted between sALCL and cALCL In contrast, expression of CD44v6 was found in 18 (90%) of sALCL cases and in 5 (50%) of cALCL cases. There was no correlation between expression of CD44v6 and expression of ALK in sALCL. These results indicate that expression of CD44v6 rather than CD44 correlates with sALCL. Furthermore, these results suggest that CD44v6 and ALK may be independent predictors of risk for the systemic phenotype of ALCL.

Pustulo-ovoid bodies of Milian in granular cell tumors.

BACKGROUND: Granular cell tumors (GCTs) are benign neural tumors with a distinct histologic appearance on light microscopy, characterized by eosinophilic cytoplasmic granules. Pustulo-ovoid bodies of Milian (POB) are larger granules surrounded by a clear halo. There have been no histologic studies to document their prevalence in GCT. METHODS: We examined the sections of 47 cases of GCT stained with hematoxylin and eosin to determine the frequency of POB within this tumor. POB were measured per 10 high-power fields (HPFs) and were divided into the following categories: less than 10 POB per 10 HPFs, 10-30 per 10 HPFs, 30-50 per 10 HPFs and greater than 50 per 10 HPFs. RESULTS: POB were present in 100% of the specimens examined. Eleven cases (23%) had between 1 and 9 POBs per 10 HPFs, twelve cases (26%) had between 10 and 29 POBs per HPFs, five cases (11%) had between 30 and 50 POBs per HPFs and nineteen cases (40%) had greater than 50 POBs per HPFs. When grouped according to clinical characteristics, there was an even distribution of POB by age, sex and site of the tumor. CONCLUSIONS: In our series, POB were present in varying numbers in all the tumors studied. They appear to represent the heterogeneity of the lysosomes, giving the appearance of large granules that have partially detached from the adjacent cytoplasm. POB are an easily recognizable component of GCTs.

Correlation of p16 and pRb expression with HPV detection in Bowen's disease.

BACKGROUND: Bowen's disease is a form of cutaneous squamous cell carcinoma which may be caused by ultraviolet radiation, human papilloma virus (HPV) infection, or other causes. Although p16 over-expression is a surrogate marker of HPV E7-mediated catabolism of pRb in premalignant and malignant lesions of the cervical mucosa, the correlation of p16 and pRb expression with HPV detection in Bowen's disease has not been well characterized. METHODS: A retrospective study on formalin-fixed tissues was performed. Immunohistochemistry for p16 and pRb was performed on 32 cases. DNA was successfully extracted from 20 cases, and polymerase chain reaction was performed to amplify a highly conserved region of the HPV L1 open reading frame. RESULTS: Twenty-eight of 32 (88%) cases showed strong diffuse staining for p16 but were negative for pRb; two of 32 cases (6%) were negative for p16 but were diffusely positive for pRb; one case was strongly positive for both p16 and pRb, and one case was negative for both p16 and pRb. Three of 20 cases (15%) contained HPV DNA. All three of these cases showed strong p16 expression and lack of pRb staining. CONCLUSIONS: Most cases of Bowen's disease strongly express p16 but not pRb. In contrast to HPV-associated lesions of the cervical mucosa, p16 overexpression in cutaneous Bowen's disease appears to be unrelated to HPV status. The p16 overexpression in Bowen's disease may reflect disruption of the G1/S checkpoint, resulting in unregulated cell cycle progression.

Vulvar clear cells of Toker: precursors of extramammary Paget's disease.

Clear cells of Toker are intraepithelial cells with clear to pale staining cytoplasm and bland cytologic features found with H&E staining in approximately 10% of normal nipples. Toker cells have been hypothesized as a precursor of extramammary Paget's disease (EMPD), although Toker cells have not been identified as a normal component of genital skin. Using immunohistochemistry, we studied 11 vulvectomies for the presence of Toker cells in association with mammary-like glands of the vulva (MLG). A retrospective study of 11 vulvectomies was performed using routine hematoxylin and eosin staining, as well as immunohistochemical staining for cytokeratin 7 (CK7). Control sections of skin not involving the milk line from age-matched patients were also examined. Four of eleven vulvectomies (36%) demonstrated Toker cells with CK7 staining. Toker cells were associated with the openings of the ducts of mammary-like glands of the vulva. Toker cells were not seen in control tissues. Toker cells occur as a normal constituent of genital skin in association with mammary-like glands of the vulva. Previous morphologic, immunohistochemical, and ultrastructural evidence have pointed to Toker cells as a precursor of EMPD. The demonstration of Toker cells in genital skin strengthens the evidence of their role in the development of EMPD.

Clear cells of Toker in accessory nipples.

BACKGROUND: Clear cells of Toker are intraepithelial cells with clear to pale staining cytoplasm and bland cytologic features found in approximately 10% of normal nipples. Toker cells have been hypothesized as a precursor of extramammary Paget's disease (EMPD), although the distribution of Toker cells outside of the nipples has not been studied. Using immunohistochemistry, we studied 20 cases of accessory nipples for the presence of Toker cells. METHODS: A retrospective study of 20 cases of accessory nipples was performed using routine hemotoxylin and eosin staining, as well as immunohistochemical staining for CK7, CK20, EMA, and GCDFP-15. RESULTS: Thirteen out of 20 accessory nipples (65%) demonstrated Toker cells with CK7 staining. Toker cells in six of the 13 cases were also positive for EMA. Only one case with Toker cells showed immunoreactivity for antibodies to GCDFP-15. CONCLUSIONS: Toker cells occur outside the normal nipple epidermis in the epidermis of accessory nipples. The distribution of Toker cells along the milk line correlates with the distribution of most cases of EMPD along the milk line, especially in the groin and axillae. Further studies are necessary to define the relationship between Toker cells and EMPD.

Expression of CD44 and CD44v6 in primary cutaneous CD30 positive T-cell lymphoproliferative disorders.

BACKGROUND: Expression of the lymphocyte homing receptor CD44 and its variant form, CD44v6, have been linked to unfavorable prognosis and tumor dissemination in non-Hodgkin's lymphoma. The role of CD44 and CD44v6 in primary cutaneous lymphomas may not necessarily correlate with that observed in nodal lymphomas. Our study attempts to evaluate the expression pattern of CD44 and CD44v6 in primary cutaneous CD30 positive T-cell lymphoproliferative disorders including primary cutaneous anaplastic large cell lymphoma (cALCL) and lymphomatoid papulosis (LyP) and compared the expression between these two subgroups. METHODS: Immunohistochemical staining of CD44 and CD44v6 was performed on 10 cALCL and 18 LyP cases. RESULTS: CD44 consistently expressed in all cases of primary cutaneous CD30 positive T-cell lymphoproliferative disorders. In contrast with previous studies, our results showed that CD44v6 expressed in 46% of all cases, including 50% cALCL and 44% LyP. There was no statistic difference in expression of CD44 or CD44v6 between cALCL and LyP subgroups. CONCLUSIONS: These results provide a new evidence that CD44v6 is expressed in a subset cases of primary cutaneous CD30 positive T-cell lymphoproliferative disorders and suggest that other factors or molecules rather than CD44 or CD44v6 are responsible for the difference between cALCL and LyP.

Vancomycin-associated linear IgA bullous dermatosis mimicking toxic epidermal necrolysis.

Vancomycin is the most frequent trigger of drug-induced linear IgA bullous dermatosis. We describe a fulminant case of linear IgA bullous dermatosis in a 74-year-old man who experienced skin sloughing of 90% of his body surface after receiving vancomycin.